The broad objective of the proposed research is to detect gene effects in bipolar and related affective disorders. This goal will be attained by 1. collecting extended high-density pedigrees segregating these disorders; 2. characterizing the clinical phenotype using comprehensive clinical ratings and operational diagnostic criteria; 3. conducting linkage studies with DNA markers; and 4. re-evaluating the linkage results in previously identified pedigrees with evidence of X-linked transmission by extending and updating the clinical and genetic information. Pending the results of the linkage analyses, long-range goals will include: identification and characterization of the disease gene(s); characterization of linked disease forms on clinical and biological measures; elucidation of gene-environment interaction; expansion of the pedigree roster to replicate linkage results and to assess etiologic heterogeneity; and a follow-up study aimed at extending and updating the pedigrees already identified. Three populations will be studied: a general North-American sample; a Jewish-American (Hasidic) 'isolate'; and an Israeli sample. This should allow assessment of genetic and cultural differences among populations. The availability of a unique series of pedigrees, coupled with recent advances in diagnostic procedures, molecular genetic techniques, and linkage analysis, holds promise for unraveling the genetic mechanisms that underlie some forms of major affective illness. This, in turn, may have important implications for the etiology, nosology, pathophysiology and, possibly, prevention and treatment and treatment of these disorders. The candidate's continued professional growth will be sustained and fostered by 1. the experience to be gained during the conduct of the proposed research; 2. extensive collaborations and consultations with other experts in the field; 3. courses, seminars and workshops in the relevant disciplines; and 4. utilization of unique departmental resources and environment dedicated to psychiatric genetics.